Endogenous cannabinoids (endocannabinoids) serve as retrograde messengers at synapses in various regions of the brain. The family of endocannabinoids includes at least five derivatives of arachidonic acid; the two best characterized are arachydonoyl ethanolamide (anandamide, AEA) and 2-arachydonoil glycerol (2AG). They are released from postsynaptic neurons upon postsynaptic depolarization and/or receptor activation. The released endocannabinoids then activate the CB1 receptors (CB1R) at presynaptic terminals and suppress the release of inhibitory transmitter GABA (depolarization-induced suppression of inhibition, DSI) or excitatory transmitter glutamate (depolarization-induced suppression of excitation, DSE) by inhibiting Ca2+ channels. Whereas DSI and DSE result in short-term synaptic plasticity, endocannabinoids also mediate long-term synaptic changes (eCB-LTD). Persistent activation of CB1 receptors over a period of minutes triggers eCB-LTD by a RIM1alpha-dependent mechanism.